EP3521271B1 - Pseudo-ceramide compound and preparation method therefor - Google Patents
Pseudo-ceramide compound and preparation method therefor Download PDFInfo
- Publication number
- EP3521271B1 EP3521271B1 EP17856615.4A EP17856615A EP3521271B1 EP 3521271 B1 EP3521271 B1 EP 3521271B1 EP 17856615 A EP17856615 A EP 17856615A EP 3521271 B1 EP3521271 B1 EP 3521271B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- chemical formula
- hydroxymethyl
- amide
- pseudo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
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- 229940106189 ceramide Drugs 0.000 title claims description 42
- 238000002360 preparation method Methods 0.000 title description 24
- 239000000126 substance Substances 0.000 claims description 75
- 150000001875 compounds Chemical class 0.000 claims description 62
- -1 ethylidene, isopropylidene, cyclohexylidene, benzylidene Chemical group 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 11
- HNTGIJLWHDPAFN-UHFFFAOYSA-N 1-bromohexadecane Chemical compound CCCCCCCCCCCCCCCCBr HNTGIJLWHDPAFN-UHFFFAOYSA-N 0.000 claims description 10
- VJSMAVXRJFSBRE-UHFFFAOYSA-N N-[1-hexadecoxy-3-hydroxy-2-(hydroxymethyl)propan-2-yl]tetradecanamide Chemical compound C(CCCCCCCCCCCCCCC)OCC(CO)(CO)NC(CCCCCCCCCCCCC)=O VJSMAVXRJFSBRE-UHFFFAOYSA-N 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- WSULSMOGMLRGKU-UHFFFAOYSA-N 1-bromooctadecane Chemical compound CCCCCCCCCCCCCCCCCCBr WSULSMOGMLRGKU-UHFFFAOYSA-N 0.000 claims description 5
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 claims description 5
- KOFZTCSTGIWCQG-UHFFFAOYSA-N 1-bromotetradecane Chemical compound CCCCCCCCCCCCCCBr KOFZTCSTGIWCQG-UHFFFAOYSA-N 0.000 claims description 4
- CPGAGIXOVBLPED-UHFFFAOYSA-N N-[1-hexadecoxy-3-hydroxy-2-(hydroxymethyl)propan-2-yl]hexadecanamide Chemical compound C(CCCCCCCCCCCCCCC)OCC(CO)(CO)NC(CCCCCCCCCCCCCCC)=O CPGAGIXOVBLPED-UHFFFAOYSA-N 0.000 claims description 4
- LVPQYWUONPGZHK-UHFFFAOYSA-N N-[1-hexadecoxy-3-hydroxy-2-(hydroxymethyl)propan-2-yl]octadecanamide Chemical compound C(CCCCCCCCCCCCCCC)OCC(CO)(CO)NC(CCCCCCCCCCCCCCCCC)=O LVPQYWUONPGZHK-UHFFFAOYSA-N 0.000 claims description 4
- UNSAJINGUOTTRA-UHFFFAOYSA-N 3-(3-bromophenyl)prop-2-yn-1-ol Chemical compound OCC#CC1=CC=CC(Br)=C1 UNSAJINGUOTTRA-UHFFFAOYSA-N 0.000 claims description 3
- SBVABCNICNYNAL-UHFFFAOYSA-N N-[1-hydroxy-2-(hydroxymethyl)-3-octadecoxypropan-2-yl]hexadecanamide Chemical compound OCC(COCCCCCCCCCCCCCCCCCC)(CO)NC(CCCCCCCCCCCCCCC)=O SBVABCNICNYNAL-UHFFFAOYSA-N 0.000 claims description 3
- ILLSMDCXTXMAIN-UHFFFAOYSA-N N-[1-hydroxy-2-(hydroxymethyl)-3-octadecoxypropan-2-yl]octadecanamide Chemical compound OCC(COCCCCCCCCCCCCCCCCCC)(CO)NC(CCCCCCCCCCCCCCCCC)=O ILLSMDCXTXMAIN-UHFFFAOYSA-N 0.000 claims description 3
- NKCQOJNPLZDFQG-UHFFFAOYSA-N N-[1-hydroxy-2-(hydroxymethyl)-3-octadecoxypropan-2-yl]tetradecanamide Chemical compound OCC(COCCCCCCCCCCCCCCCCCC)(CO)NC(CCCCCCCCCCCCC)=O NKCQOJNPLZDFQG-UHFFFAOYSA-N 0.000 claims description 3
- HHLFRJLQRUZNLL-UHFFFAOYSA-N N-[1-hydroxy-2-(hydroxymethyl)-3-tetradecoxypropan-2-yl]hexadecanamide Chemical compound OCC(COCCCCCCCCCCCCCC)(CO)NC(CCCCCCCCCCCCCCC)=O HHLFRJLQRUZNLL-UHFFFAOYSA-N 0.000 claims description 3
- RFFWTZXCGNCZBD-UHFFFAOYSA-N N-[1-hydroxy-2-(hydroxymethyl)-3-tetradecoxypropan-2-yl]octadecanamide Chemical compound OCC(COCCCCCCCCCCCCCC)(CO)NC(CCCCCCCCCCCCCCCCC)=O RFFWTZXCGNCZBD-UHFFFAOYSA-N 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- WTBAHSZERDXKKZ-UHFFFAOYSA-N octadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCC(Cl)=O WTBAHSZERDXKKZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001118 alkylidene group Chemical group 0.000 claims description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 20
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 20
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 20
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 210000000434 stratum corneum Anatomy 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- 210000003491 skin Anatomy 0.000 description 6
- 239000002537 cosmetic Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- RDTFPIIJZRSCJE-UHFFFAOYSA-N N-[5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl]hexadecanamide Chemical compound OCC1(COC(OC1)(C)C)NC(CCCCCCCCCCCCCCC)=O RDTFPIIJZRSCJE-UHFFFAOYSA-N 0.000 description 4
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- FZKNPLIAARFREX-UHFFFAOYSA-N (5-amino-2,2-dimethyl-1,3-dioxan-5-yl)methanol Chemical compound CC1(C)OCC(N)(CO)CO1 FZKNPLIAARFREX-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- NSXVGHOFIIBCEW-UHFFFAOYSA-N N-[5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl]octadecanamide Chemical compound OCC1(COC(OC1)(C)C)NC(CCCCCCCCCCCCCCCCC)=O NSXVGHOFIIBCEW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000008591 skin barrier function Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-O Htris Chemical compound OCC([NH3+])(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-O 0.000 description 2
- 241000446313 Lamella Species 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- RYMTVSKZWKWXMU-UHFFFAOYSA-N N-[5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl]tetradecanamide Chemical compound OCC1(COC(OC1)(C)C)NC(CCCCCCCCCCCCC)=O RYMTVSKZWKWXMU-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 150000002009 diols Chemical group 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 150000002632 lipids Chemical group 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 2
- 150000000185 1,3-diols Chemical class 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical group CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 1
- VOWWBXOCUUQXGG-HSOILSAZSA-N CCCCCC[C@H]1OC1N(C)C(C)O Chemical compound CCCCCC[C@H]1OC1N(C)C(C)O VOWWBXOCUUQXGG-HSOILSAZSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001241 acetals Chemical group 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000003855 acyl compounds Chemical class 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 description 1
- 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- 125000005066 dodecenyl group Chemical group C(=CCCCCCCCCCC)* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 125000005064 octadecenyl group Chemical group C(=CCCCCCCCCCCCCCCCC)* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000003014 reinforcing effect Effects 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 125000005063 tetradecenyl group Chemical group C(=CCCCCCCCCCCCC)* 0.000 description 1
- 125000005040 tridecenyl group Chemical group C(=CCCCCCCCCCCC)* 0.000 description 1
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/68—Sphingolipids, e.g. ceramides, cerebrosides, gangliosides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B51/00—Introduction of protecting groups or activating groups, not provided for in the preceding groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a novel pseudo-ceramide compound and a preparation method thereof.
- stratum corneum The surface of human skin is protected by stratum corneum.
- stratum corneum intercellular lipid forms a lamella structure and contributes to maintain skin's basic function.
- the stratum corneum intercellular lipid consists of ceramide, cholesterol, free fatty acid and the like.
- the ceramide is a main component and plays a central role in moisture retention and barrier function of the stratum corneum. It is known that if the content of ceramide in the stratum corneum is reduced, the protective barrier function of the stratum corneum is reduced and various skin diseases are exacerbated.
- the ceramide is extracted from various plants and animals containing the ceramide.
- the natural ceramide is not suitable for commercialization because it is difficult to mass-produce and the raw material is expensive due to difficulty of extraction and the like.
- the natural ceramide is low in solubility in various solvents used in cosmetics, and thus the natural ceramide is limited in the amount that can be used when preparing a product and there is a limit to obtaining efficacy.
- Patent Document 1 Korean Laid-open Patent Publication No. 2014-0070474 , NOVEL PSEUDO-CERAMIDE COMPOUND AND METHOD FOR PREPARING THE SAME.
- the present inventors have made efforts to synthesize a pseudo-ceramide compound having improved physical properties such as solubility while having a structure similar to the natural ceramide, and as a result, has completed the present invention.
- the present invention provides a pseudo-ceramide compound represented by the following Chemical Formula 1: wherein R 1 and R 2 are as described in the specification.
- the present invention provides a method for preparing a pseudo-ceramide compound, which is represented by the following Reaction Scheme 1 and comprises the steps of
- the pseudo-ceramide compound has a molecular structure and a function similar to those of the natural ceramide, can be readily synthesized, and has excellent solubility and stability in an organic solvent, and thus can be used as an alternative to the natural ceramide. Therefore, the pseudo-ceramide compound of the present invention can be widely applied to a skin preparation for external use, a cosmetic composition, and the like for reinforcing and maintaining a skin barrier function.
- the present invention provides a novel pseudo-ceramide compound represented by the following Chemical Formula 1: wherein R 1 and R 2 are the same as or different from each other and are each independently a C9 to C23 saturated or unsaturated aliphatic chain.
- the C9 to C23 saturated aliphatic chain referred to in the present specification is a chain in which the carbon-carbon bond is composed of only single bonds, and may be, for example, but is not limited to, nonanyl (C9:0), decanyl (C10:0), undecanyl (C11:0), dodecanyl (C12:0), tridecanyl (C13:0), tetradecanyl (C14:0), pentadecanyl (C15:0), hexadecanyl (C16:0), heptadecanyl (C17:0), octadecanyl (C18:0), nonadecanyl (C19:0), icosanyl (C20:0), henicosanyl (C21:0), docosanyl (C22:0), or tricosanyl (C23:0).
- the C9 to C23 unsaturated aliphatic chain referred to in the present specification is a chain including at least one carbon-carbon double or triple bond, and may be, for example, but is not limited to, nonenyl (C9:1), decenyl (C10:1), undecenyl (C11:1), dodecenyl(C12:1), tridecenyl (C13:1), tetradecenyl (C14:1), pentadecenyl (C15:1), hexadecenyl (C16:1), heptadecenyl (C17:1), octadecenyl (C18:1), nonadecenyl (C19:1), icosenyl (C20:1), henicosenyl (C21:1) docosenyl (C22:1), or tricosenyl (C23:1).
- nonenyl C9:1
- R 1 and R 2 are the same as or different from each other, and each independently can be a C13 to C18 saturated or unsaturated aliphatic chain.
- R 1 and R 2 are the same as or different from each other, and each independently may be tridecanyl, tetradecanyl, pentadecanyl, hexadecanyl, heptadecanyl, or octadecanyl.
- R 1 may be tridecanyl, pentadecanyl, or heptadecanyl
- R 2 may be tetradecanyl, hexadecanyl, or octadecanyl.
- Specific examples of the compound represented by Chemical Formula 1 may include hexadecanoic acid (2-hexadecyloxy-1,1-bis-hydroxymethyl-ethyl)-amide (Chemical Formula 8), hexadecanoic acid (1,1-bis-hydroxymethyl-2-tetradecyloxy-ethyl)-amide (Chemical Formula 9), hexadecanoic acid (1,1-bis-hydroxymethyl-2-octadecyloxy-ethyl)-amide (Chemical Formula 10), octadecanoic acid (2-hexadecyloxy-1,1-bis-hydroxymethyl-ethyl)-amide (Chemical Formula 11), octadecanoic acid (1,1-bis-hydroxymethyl-2-tetradecyloxy-ethyl)-amide (Chemical Formula 12), octadecanoic acid (1,1-bis-hydroxymethyl-2-octadecyloxy-e
- the pseudo-ceramide compound of Chemical Formula 1 as described above is structurally and functionally similar to the natural ceramide, and thus can be used as a raw material of the skin preparation for external use or cosmetic composition for skin barrier protection.
- the pseudo-ceramide compound according to the present invention can be synthesized using 2-amino-2-hydroxymethyl-propane-1,3-diol as a starting material.
- the present invention provides a method for preparing the pseudo-ceramide compound, which is represented by the following Reaction Scheme 1 and comprises the steps of
- the C1 to C4 acyloxy may be formate, acetate, propionate or butanoate, and the C1 to C4 alkoxy may be methoxy, ethoxy, propoxy, isopropoxy or butoxy.
- the L 1 is Cl.
- step S1 a protecting group is introduced into tris (hydroxymethyl) aminomethane (2-amino-2-hydroxymethyl-propane-1,3-diol, Chemical Formula 2) to prepare a compound of Chemical Formula 3 in which 1,3-diols are protected.
- the protecting group can be used without limitation as long as it is used as a protecting group of a hydroxy group. However, it is desirable to use a protecting group that is used as a diol protecting group so that two of the three hydroxy groups of tris(hydroxymethyl)aminomethane can be protected simultaneously. Specifically, methylidene acetal, ethylidene acetal, isopropylidene ketal, cyclohexylidene ketal, benzylidene ketal, or p-methoxybenzylidene acetal protecting group may be used.
- the solvent used in this step is preferably an organic solvent, and for example, may be one selected from the group consisting of chloroform, dimethylformamide (DMF), dichloromethane, diisopropyl ether, diethylether, tetrahydrofuran (THF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), chlorobenzene, toluene, benzene, acetone, and mixed solvents thereof.
- organic solvent for example, may be one selected from the group consisting of chloroform, dimethylformamide (DMF), dichloromethane, diisopropyl ether, diethylether, tetrahydrofuran (THF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), chlorobenzene, toluene, benzene, acetone, and mixed solvents thereof.
- reaction conditions temperature, pressure, time and the like are not particularly limited in the present invention, but are in accordance with known conditions.
- the protecting group is an isopropylidene ketal protecting group.
- the method of introducing the isopropylidene ketal protecting group is not particularly limited in the present invention, and a method known in the art can be used.
- the isopropylidene ketal protecting group can be introduced by reacting tris(hydroxymethyl)aminomethane with 2,2-dimethoxypropane under a slightly acidic condition, as shown in the following Reaction Scheme 2.
- the above-mentioned organic solvent may be used, and an acid catalyst may be used.
- an acid catalyst may be used.
- DMF as a solvent
- p-toluene sulfonic acid (TsOH) as an acid catalyst can be used.
- step S2 the compound of Chemical Formula 3 prepared by introducing the protecting group in Step S1 is reacted with a compound of Chemical Formula 4 to prepare a compound of Chemical Formula 5 having an amide group.
- the compound of Chemical Formula 4 is an acyl compound having a leaving group (L 1 ), and may be an acyl halide, an acid anhydride, or an ester.
- the compound of Chemical Formula 4 can be used without limitation as long as it satisfies the definition of Reaction Scheme 1 above, and for example, may be palmitoyl chloride (CH 3 (CH 2 ) 14 COCl), myristoyl chloride (CH 3 (CH 2 ) 12 COCl), stearoyl chloride (CH 3 (CH 2 ) 16 COCl) and the like.
- the solvent used in this step is preferably the organic solvent as described above in Step S1, and if necessary, a basic catalyst such as triethylamine, N,N'-diisopropylethylamine, pyridine or N-methylmorpholine can be used.
- a basic catalyst such as triethylamine, N,N'-diisopropylethylamine, pyridine or N-methylmorpholine.
- dichloromethane as a solvent and triethylamine as a base catalyst can be used.
- the compound of Chemical Formula 5 can be prepared by adding the base catalyst to the compound of Chemical Formula 3 at 0°C, adding the compound of Chemical Formula 4 slowly thereto, and stirring at room temperature for 2 to 4 hours.
- step S3 an aliphatic chain is introduced into the hydroxy group of the compound of Chemical Formula 5 to prepare a compound of Chemical Formula 7 having a ceramide-like structure.
- the compound of Chemical Formula 6, which is a reactant in this step, is a C9 to C23 alkyl halide, and can be used without limitation as long as it satisfies the definition of Reaction Scheme 1 above.
- the compound of Chemical Formula 6 may be bromotetradecane, bromohexadecane, bromooctadecane or the like.
- This step can be carried out using a solvent and a base catalyst used in the nucleophilic substitution reaction.
- a solvent and a base catalyst used in the nucleophilic substitution reaction.
- t-butanol, THF or 1,4-dioxane may be used as a solvent
- t-butoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide or sodium hydride may be used as a base catalyst.
- reaction conditions are not particularly limited in the present invention and can be appropriately controlled depending on the reactants used.
- t-butanol was used as a solvent
- potassium t-butoxide was used as a base catalyst
- the compound of Chemical Formula 7 was prepared by reacting at room temperature for 10 to 14 hours.
- Step S4 is a step of removing the diol protecting group introduced in step S1, and the reaction conditions, temperature, pressure, time and the like are not particularly limited and may vary depending on the protecting group used. Specifically, the removal of the protecting group may be accomplished by treatment of the acidic aqueous solution, addition of hydrogen gas in the presence of a metal catalyst.
- an acidic aqueous solution is used to remove the acetonide protecting group.
- the acid used may be hydrochloric acid, nitric acid, sulfuric acid, or acetic acid, preferably hydrochloric acid.
- the conditions for the removal reaction of the protecting group are not particularly limited in the present invention, and the reaction is carried out at a temperature of -30 to 60°C, preferably -30 to 40°C for 0.5 to 72 hours, preferably 1 to 12 hours.
- the solvent may be a polar solvent capable of dissolving an acid, and may be one selected from the group consisting of water, C1-C4 lower alcohol, tetrahydrofuran and a mixed solvent thereof, preferably tetrahydrofuran.
- the compound of Chemical Formula 1 prepared by the above-mentioned method can be applied to various fields, and can be widely applied to cosmetics, medicines, preparations for external use, foods and the like to which existing natural ceramide, synthetic ceramide or pseudo ceramide is applied.
- Example 1 Preparation of hexadecanoic acid (2-hexadecyloxy-1,1-bis-hydroxymethyl-ethyl)-amide
- reaction solution was stirred at room temperature for 3 hours, and then washed with dilute hydrochloric acid solution and saturated sodium chloride solution.
- organic solution layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain 2.5 g of a white solid.
- reaction mixture was dissolved in tetrahydrofuran (20 mL), a 1 M aqueous hydrochloric acid solution (4 mL) was added, and the mixture was stirred at room temperature for 12 hours.
- the reaction solution was diluted with dichloromethane and washed with a saturated sodium hydrogen carbonate solution.
- the organic solution layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
- the product was isolated using column chromatography to obtain 0.88 g of the desired compound as a white solid.
- 1.8 g of the desired compound was obtained using substantially the same method as in (2) of Example 1, except that octadecanoic acid (5-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-5-yl)-amide (5.0g) prepared in the above (1) was used instead of hexadecanoic acid (5-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-5-yl)-amide, tetrahydrofuran (100 mL) was used instead of t-butanol, and KOtBu (1.73g) and bromohexadecane (3.6g) were used.
- 1.1 g of the desired compound was obtained using substantially the same method as in (2) of Example 4, except that bromooctadecane (3.14g) was used instead of bromohexadecane (3.6g), and octadecanoic acid (5-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-5-yl)-amide (4.0g) and KOtBu (1.38g) were used.
- 1.2 g of the desired compound was obtained using substantially the same method as in (2) of Example 1, except that tetradecanoic acid (5-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-5-yl)-amide (3.71g) as prepared in (1) above was used instead of hexadecanoic acid (5-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-5-yl)-amide, tetrahydrofuran (100mL) was used instead of t-butanol, and KOtBu (1.47g) and bromohexadecane (2.74g) were used.
Description
- The present application claims the benefit of priority based on Korean Patent Application No.
10-2016-0124064 filed on September 27, 2016 - The present invention relates to a novel pseudo-ceramide compound and a preparation method thereof.
- The surface of human skin is protected by stratum corneum. Among the constituents of stratum corneum, stratum corneum intercellular lipid forms a lamella structure and contributes to maintain skin's basic function.
- The stratum corneum intercellular lipid consists of ceramide, cholesterol, free fatty acid and the like. Among them, the ceramide is a main component and plays a central role in moisture retention and barrier function of the stratum corneum. It is known that if the content of ceramide in the stratum corneum is reduced, the protective barrier function of the stratum corneum is reduced and various skin diseases are exacerbated.
- Meanwhile, it has been reported that if the stratum corneum is damaged by skin aging or external stimuli and thus the content of ceramide in the stratum corneum is reduced, the skin's lamella structure can be restored by supplementing ceramide from the outside and thus the skin can be restored to its normal state. Accordingly, for the purpose of restoring and maintaining skin barrier function and enhancing moisturizing power, the development of cosmetic composition containing the ceramide is actively being done.
- The ceramide is extracted from various plants and animals containing the ceramide. However, the natural ceramide is not suitable for commercialization because it is difficult to mass-produce and the raw material is expensive due to difficulty of extraction and the like. In addition, the natural ceramide is low in solubility in various solvents used in cosmetics, and thus the natural ceramide is limited in the amount that can be used when preparing a product and there is a limit to obtaining efficacy.
- Therefore, in order to replace the natural ceramide, it is necessary to research and develop a pseudo-ceramide compound which has a structure similar to the natural ceramide, is easy to synthesize, and has improved physical properties.
- (Patent Document 1) Korean Laid-open Patent Publication No.
2014-0070474 - In order to solve the above problems, the present inventors have made efforts to synthesize a pseudo-ceramide compound having improved physical properties such as solubility while having a structure similar to the natural ceramide, and as a result, has completed the present invention.
- Therefore, it is an object of the present invention to provide a novel pseudo-ceramide compound and a preparation method thereof.
-
- In addition, the present invention provides a method for preparing a pseudo-ceramide compound, which is represented by the following Reaction Scheme 1 and comprises the steps of
- S1) introducing a protecting group into a compound of Chemical Formula 2 to prepare a compound of Chemical Formula 3;
- S2) reacting the compound of Chemical Formula 3 with a compound of Chemical Formula 4 to prepare a compound of Chemical Formula 5;
- S3) reacting the compound of Chemical Formula 5 with a compound of Chemical Formula 6 under a base catalyst to prepare a compound of Chemical Formula 7; and
- S4) removing the protecting group from the compound of Chemical Formula 7 to prepare a compound of Chemical Formula 1:
- According to the present invention, the pseudo-ceramide compound has a molecular structure and a function similar to those of the natural ceramide, can be readily synthesized, and has excellent solubility and stability in an organic solvent, and thus can be used as an alternative to the natural ceramide. Therefore, the pseudo-ceramide compound of the present invention can be widely applied to a skin preparation for external use, a cosmetic composition, and the like for reinforcing and maintaining a skin barrier function.
- Hereinafter, the present invention will be described in detail so as to be easily carried out by those having ordinary skill in the art to which the present invention pertains. However, the present invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.
-
- The C9 to C23 saturated aliphatic chain referred to in the present specification is a chain in which the carbon-carbon bond is composed of only single bonds, and may be, for example, but is not limited to, nonanyl (C9:0), decanyl (C10:0), undecanyl (C11:0), dodecanyl (C12:0), tridecanyl (C13:0), tetradecanyl (C14:0), pentadecanyl (C15:0), hexadecanyl (C16:0), heptadecanyl (C17:0), octadecanyl (C18:0), nonadecanyl (C19:0), icosanyl (C20:0), henicosanyl (C21:0), docosanyl (C22:0), or tricosanyl (C23:0).
- In addition, the C9 to C23 unsaturated aliphatic chain referred to in the present specification is a chain including at least one carbon-carbon double or triple bond, and may be, for example, but is not limited to, nonenyl (C9:1), decenyl (C10:1), undecenyl (C11:1), dodecenyl(C12:1), tridecenyl (C13:1), tetradecenyl (C14:1), pentadecenyl (C15:1), hexadecenyl (C16:1), heptadecenyl (C17:1), octadecenyl (C18:1), nonadecenyl (C19:1), icosenyl (C20:1), henicosenyl (C21:1) docosenyl (C22:1), or tricosenyl (C23:1).
- Preferably, R1 and R2 are the same as or different from each other, and each independently can be a C13 to C18 saturated or unsaturated aliphatic chain.
- More preferably, R1 and R2 are the same as or different from each other, and each independently may be tridecanyl, tetradecanyl, pentadecanyl, hexadecanyl, heptadecanyl, or octadecanyl.
- Furthermore preferably, R1 may be tridecanyl, pentadecanyl, or heptadecanyl, and R2 may be tetradecanyl, hexadecanyl, or octadecanyl.
- Specific examples of the compound represented by Chemical Formula 1 may include hexadecanoic acid (2-hexadecyloxy-1,1-bis-hydroxymethyl-ethyl)-amide (Chemical Formula 8), hexadecanoic acid (1,1-bis-hydroxymethyl-2-tetradecyloxy-ethyl)-amide (Chemical Formula 9), hexadecanoic acid (1,1-bis-hydroxymethyl-2-octadecyloxy-ethyl)-amide (Chemical Formula 10), octadecanoic acid (2-hexadecyloxy-1,1-bis-hydroxymethyl-ethyl)-amide (Chemical Formula 11), octadecanoic acid (1,1-bis-hydroxymethyl-2-tetradecyloxy-ethyl)-amide (Chemical Formula 12), octadecanoic acid (1,1-bis-hydroxymethyl-2-octadecyloxy-ethyl)-amide (Chemical Formula 13), tetradecanoic acid (2-hexadecyloxy-1,1-bis-hydroxymethyl-ethyl)-amide (Chemical Formula 14), or tetradecanoic acid (1,1-bis-hydroxymethyl-2-octadecyloxy-ethyl)-amide (Chemical Formula 15).
- The pseudo-ceramide compound of Chemical Formula 1 as described above is structurally and functionally similar to the natural ceramide, and thus can be used as a raw material of the skin preparation for external use or cosmetic composition for skin barrier protection.
- The pseudo-ceramide compound according to the present invention can be synthesized using 2-amino-2-hydroxymethyl-propane-1,3-diol as a starting material.
- Specifically, the present invention provides a method for preparing the pseudo-ceramide compound, which is represented by the following Reaction Scheme 1 and comprises the steps of
- S1) introducing a protecting group into a compound of Chemical Formula 2 to prepare a compound of Chemical Formula 3;
- S2) reacting the compound of Chemical Formula 3 with a compound of Chemical Formula 4 to prepare a compound of Chemical Formula 5;
- S3) reacting the compound of Chemical Formula 5 with a compound of Chemical Formula 6 under a base catalyst to prepare a compound of Chemical Formula 7; and
- S4) removing the protecting group from the compound of Chemical Formula 7 to prepare a compound of Chemical Formula 1:
- wherein X is alkylidene, ethylidene, isopropylidene, cyclohexylidene, benzylidene or p-methoxybenzylidene,
- R1 and R2 are the same as or different from each other and are each independently a C9 to C23 saturated or unsaturated aliphatic chain,
- L1 is Cl, Br, I, C1 to C4 acyloxy, or C1 to C4 alkoxy, and
- L2 is Cl, Br, or I.
- At this time, the C1 to C4 acyloxy may be formate, acetate, propionate or butanoate, and the C1 to C4 alkoxy may be methoxy, ethoxy, propoxy, isopropoxy or butoxy. Preferably, the L1 is Cl.
- Hereinafter, each step will be described in detail.
- In step S1, a protecting group is introduced into tris (hydroxymethyl) aminomethane (2-amino-2-hydroxymethyl-propane-1,3-diol, Chemical Formula 2) to prepare a compound of Chemical Formula 3 in which 1,3-diols are protected.
- The protecting group can be used without limitation as long as it is used as a protecting group of a hydroxy group. However, it is desirable to use a protecting group that is used as a diol protecting group so that two of the three hydroxy groups of tris(hydroxymethyl)aminomethane can be protected simultaneously. Specifically, methylidene acetal, ethylidene acetal, isopropylidene ketal, cyclohexylidene ketal, benzylidene ketal, or p-methoxybenzylidene acetal protecting group may be used.
- The solvent used in this step is preferably an organic solvent, and for example, may be one selected from the group consisting of chloroform, dimethylformamide (DMF), dichloromethane, diisopropyl ether, diethylether, tetrahydrofuran (THF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), chlorobenzene, toluene, benzene, acetone, and mixed solvents thereof.
- In this step, a known acid or base catalyst may be used if necessary. The reaction conditions, temperature, pressure, time and the like are not particularly limited in the present invention, but are in accordance with known conditions.
- According to one preferred embodiment of the present invention, the protecting group is an isopropylidene ketal protecting group. The method of introducing the isopropylidene ketal protecting group is not particularly limited in the present invention, and a method known in the art can be used. For example, the isopropylidene ketal protecting group can be introduced by reacting tris(hydroxymethyl)aminomethane with 2,2-dimethoxypropane under a slightly acidic condition, as shown in the following Reaction Scheme 2.
- In the reaction of the above Reaction Scheme 2, the above-mentioned organic solvent may be used, and an acid catalyst may be used. Preferably, DMF as a solvent and p-toluene sulfonic acid (TsOH) as an acid catalyst can be used.
- In step S2, the compound of Chemical Formula 3 prepared by introducing the protecting group in Step S1 is reacted with a compound of Chemical Formula 4 to prepare a compound of Chemical Formula 5 having an amide group.
- The compound of Chemical Formula 4 is an acyl compound having a leaving group (L1), and may be an acyl halide, an acid anhydride, or an ester. The compound of Chemical Formula 4 can be used without limitation as long as it satisfies the definition of Reaction Scheme 1 above, and for example, may be palmitoyl chloride (CH3(CH2)14COCl), myristoyl chloride (CH3(CH2)12COCl), stearoyl chloride (CH3(CH2)16COCl) and the like.
- The solvent used in this step is preferably the organic solvent as described above in Step S1, and if necessary, a basic catalyst such as triethylamine, N,N'-diisopropylethylamine, pyridine or N-methylmorpholine can be used. At this time, the reaction conditions, temperature, pressure, time and the like are not particularly limited, but are in accordance with known conditions.
- According to one preferred embodiment of the present invention, dichloromethane as a solvent and triethylamine as a base catalyst can be used. The compound of Chemical Formula 5 can be prepared by adding the base catalyst to the compound of Chemical Formula 3 at 0°C, adding the compound of Chemical Formula 4 slowly thereto, and stirring at room temperature for 2 to 4 hours.
- In step S3, an aliphatic chain is introduced into the hydroxy group of the compound of Chemical Formula 5 to prepare a compound of Chemical Formula 7 having a ceramide-like structure.
- The compound of Chemical Formula 6, which is a reactant in this step, is a C9 to C23 alkyl halide, and can be used without limitation as long as it satisfies the definition of Reaction Scheme 1 above. Specifically, the compound of Chemical Formula 6 may be bromotetradecane, bromohexadecane, bromooctadecane or the like.
- This step can be carried out using a solvent and a base catalyst used in the nucleophilic substitution reaction. Specifically, t-butanol, THF or 1,4-dioxane may be used as a solvent, and t-butoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide or sodium hydride may be used as a base catalyst.
- At this time, the reaction conditions, temperature, pressure, time and the like are not particularly limited in the present invention and can be appropriately controlled depending on the reactants used.
- Specifically, in one embodiment of the present invention, t-butanol was used as a solvent, and potassium t-butoxide was used as a base catalyst, and the compound of Chemical Formula 7 was prepared by reacting at room temperature for 10 to 14 hours.
- Step S4 is a step of removing the diol protecting group introduced in step S1, and the reaction conditions, temperature, pressure, time and the like are not particularly limited and may vary depending on the protecting group used. Specifically, the removal of the protecting group may be accomplished by treatment of the acidic aqueous solution, addition of hydrogen gas in the presence of a metal catalyst.
- According to one preferred embodiment of the present invention, an acidic aqueous solution is used to remove the acetonide protecting group. At this time, the acid used may be hydrochloric acid, nitric acid, sulfuric acid, or acetic acid, preferably hydrochloric acid.
- The conditions for the removal reaction of the protecting group are not particularly limited in the present invention, and the reaction is carried out at a temperature of -30 to 60°C, preferably -30 to 40°C for 0.5 to 72 hours, preferably 1 to 12 hours.
- The solvent may be a polar solvent capable of dissolving an acid, and may be one selected from the group consisting of water, C1-C4 lower alcohol, tetrahydrofuran and a mixed solvent thereof, preferably tetrahydrofuran.
- The compound of Chemical Formula 1 prepared by the above-mentioned method can be applied to various fields, and can be widely applied to cosmetics, medicines, preparations for external use, foods and the like to which existing natural ceramide, synthetic ceramide or pseudo ceramide is applied.
- Hereinafter, the present invention will be described in more detail with reference to the following Examples.
-
- (5-amino-2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (1.61g), which was synthesized according to a method known in the literature (Helv. Chim. Acta 2003, 86, 2458-2470) using 2-amino-2-hydroxymethyl-propane-1,3-diol hydrochloride as starting material, was dissolved in dichloromethane (50 mL), and after adding triethylamine (1.7 mL), palmitoyl chloride (2.75 g) dissolved in dichloromethane (10 mL) while stirring at 0 °C, was slowly added dropwise. The reaction solution was stirred at room temperature for 3 hours, and then washed with dilute hydrochloric acid solution and saturated sodium chloride solution. The organic solution layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain 2.5 g of a white solid.
- 1H NMR (300MHz, CDCl3) δ 6.28 (brs, 1H), 5.18 (m, 1H), 3.83 (s, 4H), 3.65 (d, 2H, J = 6.3Hz), 2.28 (t, 2H, J = 7.2Hz), 1.65 ∼ 1.25 (m, 32H), 0.88 (t, 3H, J = 6.9Hz).
-
- The hexadecanoic acid (5-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-5-yl)-amide (2.0 g) prepared in the above (1) was dissolved in t-butanol (50mL) and KOtBu (=potassium t-butoxide) (0.67 g) was slowly added thereto, followed by stirring at room temperature for 10 minutes. To this solution, bromohexadecane (1.53 g) was added, and further stirred for 12 hours. The reaction solution was neutralized with diluted hydrochloric acid to quench the reaction and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The reaction mixture was dissolved in tetrahydrofuran (20 mL), a 1 M aqueous hydrochloric acid solution (4 mL) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with dichloromethane and washed with a saturated sodium hydrogen carbonate solution. The organic solution layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product was isolated using column chromatography to obtain 0.88 g of the desired compound as a white solid.
- 1H NMR (300MHz, CDCl3) δ 6.50 (brs, 1H), 4.34 (m, 2H), 3.71 ∼ 3.45 (m, 8H), 2.55 (t, 2H, J = 7.5Hz), 1.80 ∼ 1.20 (m, 54H), 0.88 (m, 6H).
-
- 0.82 g of the desired compound was obtained using substantially the same method as in (2) of Example 1, except that bromotetradecane (1.39 g) was used instead of bromohexadecane (1.53 g).
- 1H NMR (300MHz, CDCl3) δ 6.49 (brs, 1H), 4.32 (m, 2H), 3.71 ∼ 3.43 (m, 8H), 2.42 (m, 2H), 1.80 ∼ 1.05 (m, 50H), 0.87 (m, 6H).
-
- 0.71 g of the desired compound was obtained using substantially the same method as in (2) of Example 1, except that bromooctadecane (1.67g) was used instead of bromohexadecane (1.53 g).
- 1H NMR (300MHz, CDCl3) δ 6.50 (brs, 1H), 4.33 (m, 2H), 3.71 ∼ 3.44 (m, 8H), 2.24 (t, 2H, J = 7.5Hz), 1.80 ∼ 1.20 (m, 58H), 0.88 (m, 6H).
-
- 23 g of the desired compound as a white solid was obtained using substantially the same method as in (1) of Example 1, except that 12.8 g of (5-Amino-2,2-dimethyl-[1,3]dioxan-5-yl)-methanol was used as the starting material and stearoyl chloride (24.5 g) was used instead of palmitoyl chloride (2.75 g).
- 1H NMR (300MHz, CDCl3) δ 6.28 (brs, 1H), 5.17 (m, 1H), 3.83 (s, 4H), 3.64 (d, 2H, J = 6.0Hz), 2.28 (t, 2H, J = 7.5Hz), 1.65 ∼ 1.25 (m, 36H), 0.87 (t, 3H, J = 6.6Hz).
-
- 1.8 g of the desired compound was obtained using substantially the same method as in (2) of Example 1, except that octadecanoic acid (5-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-5-yl)-amide (5.0g) prepared in the above (1) was used instead of hexadecanoic acid (5-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-5-yl)-amide, tetrahydrofuran (100 mL) was used instead of t-butanol, and KOtBu (1.73g) and bromohexadecane (3.6g) were used.
- 1H NMR (500MHz, CDCl3) δ 6.48 (brs, 1H), 3.68 ∼ 3.43 (m, 8H), 2.31 (m, 2H), 2.22 (m, 2H), 1.70 ∼ 1.20 (m, 58H), 0.85 (m, 6H).
-
- 1.2 g of the desired compound was obtained using substantially the same method as (2) of Example 4, except that bromotetradecane (3.27 g) was used instead of bromohexadecane (3.6 g).
- 1H NMR (500MHz, CDCl3) δ 6.47 (brs, 1H), 4.32 (m, 2H), 3.68 ∼ 3.31 (m, 8H), 2.22 (m, 2H), 1.61 ∼ 1.10 (m, 54H), 0.84 (m, 6H).
-
- 1.1 g of the desired compound was obtained using substantially the same method as in (2) of Example 4, except that bromooctadecane (3.14g) was used instead of bromohexadecane (3.6g), and octadecanoic acid (5-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-5-yl)-amide (4.0g) and KOtBu (1.38g) were used.
- 1H NMR (500MHz, CDCl3) δ 6.50 (brs, 1H), 3.70 ∼ 3.40 (m, 8H), 2.26 (m, 2H), 1.90 ∼ 1.15 (m, 64H), 0.88 (m, 6H).
-
- 15 g of the desired compound as a white solid was obtained using substantially the same method as in (1) of Example 1, except that 12.8 g of (5-amino-2,2-dimethyl-[1,3]dioxan-5-yl)-methanol was used as the starting material and myristoyl chloride (19.5 g) was used instead of palmitoyl chloride (2.75 g).
- 1H NMR (300MHz, CDCl3) δ 6.31 (brs, 1H), 5.20 (m, 1H), 3.85 (s, 4H), 3.67 (s, 2H), 2.31 (t, 2H, J = 7.2Hz), 1.68 ∼ 1.28 (m, 28H), 0.90 (t, 3H, J = 6.6Hz).
-
- 1.2 g of the desired compound was obtained using substantially the same method as in (2) of Example 1, except that tetradecanoic acid (5-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-5-yl)-amide (3.71g) as prepared in (1) above was used instead of hexadecanoic acid (5-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-5-yl)-amide, tetrahydrofuran (100mL) was used instead of t-butanol, and KOtBu (1.47g) and bromohexadecane (2.74g) were used.
- 1H NMR (500MHz, CDCl3) δ 6.47 (brs, 1H), 4.22 (m, 2H), 3.68 ∼ 3.32 (m, 8H), 2.24 (m, 2H), 1.80 ∼ 1.10 (m, 50H), 0.86 (m, 6H).
-
- 1.05 g of the desired compound was obtained using substantially the same method as in (2) of Example 7, except that bromooctadecane (3.3 g) was used instead of bromohexadecane.
- 1H NMR (500MHz, CDCl3) δ 6.47 (brs, 1H), 4.31 (m, 2H), 3.68 ∼ 3.43(m, 8H), 2.22 (t, 2H, J = 7.0Hz), 1.65 ∼ 1.10(m, 54H), 0.85(m, 6H).
Claims (7)
- The pseudo-ceramide compound according to claim 1, wherein R1 and R2 are the same as or different from each other and are each independently a C13 to C18 saturated or unsaturated aliphatic chain.
- The pseudo-ceramide compound according to claim 1, wherein the pseudo-ceramide compound is hexadecanoic acid (2-hexadecyloxy-1,1-bis-hydroxymethyl-ethyl)-amide, hexadecanoic acid (1,1-bis-hydroxymethyl-2-tetradecyloxy-ethyl)-amide, hexadecanoic acid (1,1-bis-hydroxymethyl-2-octadecyloxy-ethyl)-amide, octadecanoic acid (2-hexadecyloxy-1,1-bis-hydroxymethyl-ethyl)-amide, octadecanoic acid (1,1-bis-hydroxymethyl-2-tetradecyloxy-ethyl)-amide, octadecanoic acid (1,1-bis-hydroxymethyl-2-octadecyloxy-ethyl)-amide, tetradecanoic acid (2-hexadecyloxy-1,1-bis-hydroxymethyl-ethyl)-amide, or tetradecanoic acid (1,1-bis-hydroxymethyl-2-octadecyloxy-ethyl)-amide.
- A method for preparing a pseudo-ceramide compound, which is represented by the following Reaction Scheme 1 and comprises the steps ofS1) introducing a protecting group into a compound of Chemical Formula 2 to prepare a compound of Chemical Formula 3;S2) reacting the compound of Chemical Formula 3 with a compound of Chemical Formula 4 to prepare a compound of Chemical Formula 5;S3) reacting the compound of Chemical Formula 5 with a compound of Chemical Formula 6 under a base catalyst to prepare a compound of Chemical Formula 7; andS4) removing the protecting group from the compound of Chemical Formula 7 to prepare a compound of Chemical Formula 1:wherein X is alkylidene, ethylidene, isopropylidene, cyclohexylidene, benzylidene or p-methoxybenzylidene,R1 and R2 are the same as or different from each other and are each independently a C9 to C23 saturated or unsaturated aliphatic chain,L1 is Cl, Br, I, C1 to C4 acyloxy, or C1 to C4 alkoxy, andL2 is Cl, Br, or I.
- The method for preparing the pseudo-ceramide compound according to claim 4, wherein the R1 and R2 are the same as or different from each other and are each independently a C13 to C18 saturated or unsaturated aliphatic chain.
- The method for preparing the pseudo-ceramide compound according to claim 4, wherein the compound of Chemical Formula 4 is myristoyl chloride, palmitoyl chloride, or stearoyl chloride.
- The method for preparing the pseudo-ceramide compound according to claim 4, wherein the compound of Chemical Formula 6 is bromotetradecane, bromohexadecane, or bromooctadecane.
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PCT/KR2017/010087 WO2018062729A1 (en) | 2016-09-27 | 2017-09-14 | Pseudo-ceramide compound and preparation method therefor |
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KR100570810B1 (en) * | 2003-09-23 | 2006-04-28 | 주식회사 바이오씨에스 | Novel ceramide derivatives, method for preparing the same and use thereof |
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EP2927211A4 (en) | 2012-11-30 | 2016-07-20 | Amorepacific Corp | Novel pseudoceramide compound and production method for same |
KR101641702B1 (en) * | 2014-11-14 | 2016-07-21 | 애경산업(주) | Novel Pseudoceramide Compound and composition comprising it |
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